Applying a cost-based pricing model for innovative cancer treatments subject to indication expansion: A case study for pembrolizumab and daratumumab.

BACKGROUND: Expanding the indication of already approved immuno-oncology drugs presents treatment opportunities for patients but also strains healthcare systems. Cost-based pricing models are discussed as a possibility for cost containment. This study focuses on two drugs, pembrolizumab (Keytruda) and daratumumab (Darzalex), to explore the potential effect of indication broadening on the estimated price when using the cost-based pricing (CBP) model proposed by Uyl-de Groot and Löwenberg (2018). METHODS: The model was used to calculate cumulative yearly prices, cumulative prices per indication, and non-cumulative indication-based prices using inputs such as research and development (R&D) costs, manufacturing costs, eligible patient population, and a profit margin. A deterministic stepwise analysis and scenario analysis were conducted to examine how sensitive the estimated price is to the different input assumptions. RESULTS: The yearly cumulative cost-based prices (CBPs) ranged from €52 to €885 for pembrolizumab per vial and €823 to €31,941 for daratumumab per vial. Prices were higher in initial years or indications due to smaller patient populations, decreased over time or after additional indications. Sensitivity analysis showed that the number of eligible patients had the most significant impact on the estimated price. In the scenario analysis the profit margin contributed most to a higher CBPs for both drugs. Lower estimates resulted from assumed lower R&D costs. DISCUSSION: The estimated CBPs are consistently lower than Dutch list prices for pembrolizumab (€2,861), mainly resulting from larger patient populations in registered indications. However, daratumumab's list prices fall within the range of modeled CBPs depending on the year or indication (€4,766). Both CBPs decrease over time or with additional indications. The number of eligible patients and initial R&D costs have the most significant influence on the CBPs. These findings contribute to the ongoing discussions on pharmaceutical pricing, especially concerning cancer drugs with expanding indications.

Extrapolating empirical long-term survival data: the impact of updated follow-up data and parametric extrapolation methods on survival estimates in multiple myeloma.

BACKGROUND: In economic evaluations, survival is often extrapolated to smooth out the Kaplan-Meier estimate and because the available data (e.g., from randomized controlled trials) are often right censored. Validation of the accuracy of extrapolated results can depend on the length of follow-up and the assumptions made about the survival hazard. Here, we analyze the accuracy of different extrapolation techniques while varying the data cut-off to estimate long-term survival in newly diagnosed multiple myeloma (MM) patients. METHODS: Empirical data were available from a randomized controlled trial and a registry for MM patients treated with melphalan + prednisone, thalidomide, and bortezomib- based regimens. Standard parametric and spline models were fitted while artificially reducing follow-up by introducing database locks. The maximum follow-up for these locks varied from 3 to 13 years. Extrapolated (conditional) restricted mean survival time (RMST) was compared to the Kaplan-Meier RMST and models were selected according to statistical tests, and visual fit. RESULTS: For all treatments, the RMST error decreased when follow-up and the absolute number of events increased, and censoring decreased. The decline in RMST error was highest when maximum follow-up exceeded six years. However, even when censoring is low there can still be considerable deviations in the extrapolated RMST conditional on survival until extrapolation when compared to the KM-estimate. CONCLUSIONS: We demonstrate that both standard parametric and spline models could be worthy candidates when extrapolating survival for the populations examined. Nevertheless, researchers and decision makers should be wary of uncertainty in results even when censoring has decreased, and the number of events has increased.

Parasites and their impact on thick-shelled river mussels Unio crassus from two populations in Luxembourg.

The thick-shelled river mussel Unio crassus Philipsson, 1788 is a species native to many European habitats, with declining populations. The impact of parasite communities on health status of this species is poorly understood. In this study, parasites of 30 U. crassus specimens from the Our and Sauer Rivers in Luxembourg were identified morphologically and, in some cases, using molecular genetic methods. The findings were correlated to selected parameters (total length, visceral weight, shell lesions, gonadal stage). The 2 populations did not differ in shell length, visceral weight, number of males and females, gonadal scoring, shell lesions, and the occurrence of glochidia. The prevalence and infestation intensities of detected Trichodina sp., Conchophthirus sp., and freshwater mite larvae did not differ between the 2 populations, whereas the prevalence and infestation intensities of mite eggs, nymphs, and adults were significantly higher in the Sauer River. Rhipidocotyle campanula and European bitterling Rhodeus amarus larvae were only present in the Sauer. Histopathology revealed the destruction of the gonads by R. campanula and tissue damage by the mites. The only significant correlation of the selected parameters was a positive correlation between R. amarus occurrence and total length as well as a negative correlation between R. amarus occurrence and gonadal stage. In the Sauer River, 2 mussels were found to be hermaphrodites.

Treatment of sporadic Burkitt lymphoma in adults, a retrospective comparison of four treatment regimens.

Burkitt lymphoma is an aggressive B cell malignancy accounting for 1-2% of all adult lymphomas. Treatment with dose-intensive, multi-agent chemotherapy is effective but associated with considerable toxicity. In this observational study, we compared real-world efficacy, toxicity, and costs of four frequently employed treatment strategies for Burkitt lymphoma: the Lymphome Malins B (LMB), the Berlin-Frankfurt-Münster (BFM), the HOVON, and the CODOX-M/IVAC regimens. We collected data from 147 adult patients treated in eight referral centers. Following central pathology assessment, 105 of these cases were accepted as Burkitt lymphoma, resulting in the following treatment groups: LMB 36 patients, BFM 19 patients, HOVON 29 patients, and CODOX-M/IVAC 21 patients (median age 39 years, range 14-74; mean duration of follow-up 47 months). There was no significant difference between age, sex ratio, disease stage, or percentage HIV-positive patients between the treatment groups. Five-year progression-free survival (69%, p = 0.966) and 5-year overall survival (69%, p = 0.981) were comparable for all treatment groups. Treatment-related toxicity was also comparable with only hepatotoxicity seen more frequently in the CODOX/M-IVAC group (p = 0.004). Costs were determined by the number of rituximab gifts and the number of inpatients days. Overall, CODOX-M/IVAC had the most beneficial profile with regards to costs, treatment duration, and percentage of patients completing planned treatment. We conclude that the four treatment protocols for Burkitt lymphoma yield nearly identical results with regards to efficacy and safety but differ in treatment duration and costs. These differences may help guide future choice of treatment.

How to prepare a systematic review of economic evaluations for clinical practice guidelines: database selection and search strategy development (part 2/3).

INTRODUCTION: This article is part of the series "How to prepare a systematic review of economic evaluations (EES) for informing evidence-based healthcare decisions", in which a five-step approach is proposed. Areas covered: This paper focuses on the selection of relevant databases and developing a search strategy for detecting EEs, as well as on how to perform the search and how to extract relevant data from retrieved records. Expert commentary: Thus far, little has been published on how to conduct systematic review EEs. Moreover, reliable sources of information, such as the Health Economic Evaluation Database, have ceased to publish updates. Researchers are thus left without authoritative guidance on how to conduct SR-EEs. Together with van Mastrigt et al. we seek to fill this gap.

[Child maltreatment: long-term economic consequences and implications]. / Kindermishandeling: economische gevolgen op lange termijn1.

BACKGROUND: Child maltreatment occurs frequently. This has detrimental effects later in life on mental health and is linked to considerable costs due to health care use and sick leave. Self-mastery, however, is a factor that may well mitigated the effects of child maltreatment .
AIM: To quantify the long-term costs of child abuse and to test the hypothesis that self-mastery can modify the after-effects of maltreatment .
METHOD: Data were obtained from a psychiatric cohort study (n=5618). The risk factors were emotional neglect and mental, physical and sexual abuse before the age of 16.
RESULTS: When individuals are about 39 years old, the various forms of maltreatment to which they were subjected as children are associated with substantially higher health care costs and frequent absenteeism. Higher levels of self-mastery achieved in childhood were indeed associated with lower costs in adulthood.
CONCLUSION: Child maltreatment costs the Netherlands millions of euros annually because it leads to higher health care costs and more frequent sick leave. Active steps to curb child abuse are of both financial and economic significance. More training in self-mastery could perhaps be helpful, but further research is needed in this area.

Description of a new Echinorhynchid species (Acanthocephala) from the European eel, Anguilla anguilla, in Germany, with a key species of Acanthocephalus in Europe.

Acanthocephalus rhinensis n. sp. is described from the European eel. Anguilla anguilla (Linnaeus, 1758), collected in the Rhine River near the city of Karlsruhe, Germany. It is the sixth species of Acanthocephalus Koelreuther, 1771 described from European fish. Four other species are known from amphibians. The new species is distinguished from the other 5 species infecting fish by having a 1.2-mm-long proboscis armed with 15-21 rows of 13-16 hooks each, lemnisci about as long as receptacle, oblong and slightly pre-equatorial testes, and thin fusiform eggs, measuring 85-95 X 15-18 micro. Testes in the other European species are usually round to ovate, except in Ac. anguillae (Müller, 1780) Lühe, 1911 where they are also elongated but postequatorial. It aslo has an orange-brown belt encircling the anterior end of the trunk. The comparative distribution of Acanthocephalus in Europe and North America, and the validity of 2 presumably questionable species are discussed, Acanthocephalus falcatus (Froelich, 1789) Lühe, 1911 and Ac. Paronai (Cendorelli, 1897) Meyer, 1932. A dichotomus key distinguishing Ac. rhinensis from the other 9 European species is also included. The new species was only found in 3 of 390 eels examined during 11 yr; this may be related to the changing benthos community in the Rhine River.

The intestinal parasite Pomphorhynchus laevis as a sensitive accumulation indicator for the platinum group metals Pt, Pd, and Rh.

Concentrations of the platinum group elements Pt, Pd, and Rh were analyzed by adsorptive cathodic stripping voltammetry (Pt, Rh) and total-reflection X-ray fluorescence (Pd) in the intestinal helminth Pomphorhynchus laevis and its host Barbus barbus. The fish were caught in the Danube river south of the city of Budapest (Hungary) and were exposed to ground catalytic material for 28 days. Following exposure all three precious metals were taken up and accumulated in host organs and the parasites. Interestingly, in all tissues of the unexposed controls Pt was found, whereas Pd was not present in the muscle of the controls and Rh was not detectable in muscle and intestine of unexposed barbel. All metals were found at significantly higher concentrations in the acanthocephalan than in the tissues of barbel. These results are discussed with respect to the application of P. laevis as an accumulation indicator for metals.

The intestinal parasite Pomphorhynchus laevis (Acanthocephala) from barbel as a bioindicator for metal pollution in the Danube River near Budapest, Hungary.

Concentrations of As, Al, Ag, Ba, Bi, Cd, Co, Cr, Cu, Fe, Ga, Mg, Mn, Ni, Pb, Sb, Sn, Sr, Tl, V and Zn were analyzed by inductively coupled mass spectrometry (ICP-MS) in the intestinal helminth Pomphorhynchus laevis and its host Barbus barbus. The fish were caught in the Danube river downstream of the city of Budapest (Hungary). Ten out of twenty one elements analyzed were found at higher concentrations in the acanthocephalan than in different tissues (muscle, intestine, liver and kidney) of barbel. Considering the fish tissues, most of the elements were present at highest concentrations in liver, followed by kidney, intestine and muscle. Spearman correlation analyses indicate that there is competition for metals between the parasites and the host. The negative relationships between parasite number and metal levels in organs of the barbel support this hypothesis. The bioconcentration factors for Ag, As, Ba, Bi, Cu, Ga, Mn, Pb, Sr, Tl, and Zn showed that the parasites concentrated metals to a higher degree than the fish tissues. They accumulated the metals As, Cd, Cu, Fe, Ni, Pb, Sr and Zn even better than established bioindicators such as the mussel Dreissena polymorpha as revealed by data from the literature. The results presented here emphasize that acanthocephalans of fish are very useful as sentinels for metal pollution in aquatic ecosystems. Ratio of metal concentrations in the parasites and the host tissues provide additional information. Not including acanthocephalans in accumulation bioindication studies with fishes (as still customarily done) may lead to false results.

A retroperitoneal tumor as a late complication of the use of bone wax.

Ordinary bone wax was used to stop bleeding from the iliac crest after procurement of autogenous bone graft harvesting. This gave rise to a large, symptomatic retroperitoneal tumor, which had to be removed operatively 19 years later. Microscopically, a bone wax granuloma was diagnosed. As far as the authors know this is the first case reported with such late and severe clinical complications after the use of bone wax.

Monoclonal antibodies to human embryonal carcinoma cells: antigenic relationships of germ cell tumors.

Fifteen monoclonal antibodies (mAb) that show specificity for human embryonal carcinoma cells are described. C57BL/6 mice were immunized with Tera-2 embryonal carcinoma cells, and hybridomas were isolated and tested versus a set of human developmental tumor cell lines. The antigens exhibit relatively restricted and unique distributions on normal tissues as shown by immunohistochemistry. The mAbs recognize a series of differentiation antigens since their expression changes when teratocarcinoma stem cells are induced to differentiate in vitro. The expression of these molecules in germ cell and related tumors is consistent with the data obtained from in vitro cell studies. Seven of these mAbs immunoprecipitate molecules from surface labeled Tera-2 cells that show distinct molecular weights on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The antigenic phenotypes defined by the set of mAbs can be used to investigate possible pathogenetic relationships of the various testicular tumors.

Isolated unilateral adrenal hemorrhage after a motorcycle race.

A 19-year-old girl presenting with an isolated unilateral adrenal hemorrhage after a motorcycle cross-country race without evidence of direct trauma, is reported. The lesion was diagnosed by abdominal ultrasonography, and treated surgically by thoracolaparotomy. Recovery has resulted. A review of literature shows the rarity of the condition.

[Arterial thrombosis of the lower limb in patients over 80 years of age. Belgian multicentric experience concerning 802 patients]. / Arteriële thrombose van het onderste lidmaat boven de 80 jaar. Belgische multicentrische ervaring betreffende 802 patiënten.

This report concerns a joint study of fourteen centres about the treatment of arterial occlusion of the low extremity. Eight hundred and two patients older than 80 years have been studied during a period from 1 to 27 years. The operative mortality was 25.2%. There was no significant difference in mortality between emergency cases and those patients who were operated under elective conditions. Leg amputations are followed by a significant higher mortality than more conservative surgery such as arterial by-pass, sympathectomy or embolectomy. The most frequent cause of death was from cardiopulmonar origin (57%). The postoperative morbidity of cardiac, pulmonary, urinary or infectious origin was frequent (50%). Surgical complications in the true sence of the word are quite rare and their frequency is limited to 7%. The conclusion of this study is that conservative surgery such as reascularisation or sympathectomy is, whenever possible, to be preferred over amputation not only because of their lower mortality (13 to 19%) but also since they permit better revalidation of these elderly patients.